Role of the blood–cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E2produced in the brain

Authors:
Open Access
Publisher website
Google Scholar
Abstract
An increasing level of prostaglandin (PG) E2is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance ofPGE2under these pathological conditions appears to affect the concentration ofPGE2in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system ofPGE2production via microsomalPGEsynthetase‐1 (mPGES‐1), the induciblePGE2‐generating enzyme, andPGE2elimination from theCSF via the blood–CSFbarrier (BCSFB). Immunohistochemical analysis revealed thatmPGES‐1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites ofPGE2in theCSF. Thein vivoPGE2elimination clearance from theCSFwas eightfold greater than that ofd‐mannitol, which is considered to reflectCSFbulk flow. This process was inhibited by the simultaneous injection of unlabeledPGE2and β‐lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics ofPGE2uptake by the isolated choroid plexus were at least partially consistent with those ofOAT3.OAT3 was able to mediatePGE2transport with a Michaelis–Menten constant of 4.24 μM. These findings indicate that a system regulating thePGE2level in theCSFinvolvesOAT3‐mediatedPGE2uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via theBCSFBof locally produced PGE2.
Funding Information
  • Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture
  • Japan Society for the Promotion of Science, Japan

This publication has 56 references indexed in Scilit: